Metabolic regulation of cardiac ATP-sensitive K+ channels

Abstract

Activation of ATP-sensitive K+ (KATP) channels has been implicated as a cause of increased cellular K+ efflux and action potential duration (APD) shortening during myocardial ischemia, hypoxia, and selective glycolytic inhibition, since selective KATP channel antagonists partially or completely block increased cellular K+ efflux and APD shortening under these conditions. During substrate-free hypoxia or myocardial ischemia in intact rabbit ventricle, unidirectional K+ efflux rate during systole approximately doubled and APD decreased by ≈40% after 10 minutes. In patch-clamped guinea pig ventricular myocytes, similar changes could be produced by activation of <0.5% of the maximal KATP channel conductance. Furthermore, from studying the desensitizing effects of ADPi on the ATP sensitivity of KATP channels in excised inside-out patches, it was estimated that the rapid changes in the cytosolic ATP/ADP ratio during ischemia and hypoxia were of sufficient magnitude to activate KATP channels to this degree. During selective glycolytic inhibition, however, the global cytosolic ATP/ADP ratio in intact heart remained normal despite an increase in cellular K+ efflux comparable to ischemia and hypoxia. In patch-clamped saponin-permeabilized ventricular myocytes, KATP channels were preferentially suppressed by glycolytic ATP production compared to ATP generated by mitochondria or by the creatinine kinase reaction, and functional glycolytic enzymes were found to be associated with KATP channels in excised membrane patches. We hypothesize that sarcolemma-associated glycolytic enzymes may be important in maintaining a high local cytosolic ATP/ADP ratio in the vicinity of KATP channels, where sarcolemmal ATPases are tending to depress the local ATP/ADP ratio.